Prognostic impact of pathological complete response and response-adapted outcomes in patients with gastroesophageal adenocarcinoma treated with neoadjuvant or perioperative treatments: a multicentric cohort study

BACKGROUND: Pathological complete response (pCR) after neoadjuvant therapy is an established prognostic marker in several tumor types, but its significance in gastroesophageal adenocarcinoma (GEA) remains unclear. We investigated the role of pCR as a prognostic factor and as a predictive biomarker for benefit from adjuvant chemotherapy in a large real-world cohort of operable GEA. PATIENTS AND METHODS: We retrospectively analyzed data from 532 patients with histologically confirmed esophageal, gastroesophageal junction, and gastric adenocarcinoma treated with neoadjuvant therapy followed by curative surgery (2012-2024) at two European high-volume centers. Tumor regression was assessed using the Becker classification. Overall survival (OS) and disease-free survival (DFS) were analyzed with Cox regression models and stratified by treatment regimen, tumor site, and pathologically documented response (pathological response; PR). RESULTS: pCR was observed in 13% of patients and was significantly associated with improved OS [hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.13-0.40] and DFS (HR 0.29, 95% CI 0.17-0.47, both P < 0.001) in univariable analysis. In multivariable analysis, pCR remained an independent predictor of OS (HR 0.55, 95% CI 0.33-0.92, P = 0.023) and DFS (HR 0.53, 95% CI 0.32-0.89, P = 0.017) after adjustment for clinicopathological variables. Five-year OS and DFS were more than doubled in patients with pCR versus those without pCR (79% versus 39% and 73% versus 39%, respectively). No survival benefit from adjuvant chemotherapy was observed among patients with pCR. In contrast, those with partial or poor PR (Becker tumor regression grade 1b-3) derived significant benefit from post-operative chemotherapy for both OS and DFS (P < 0.001). CONCLUSIONS: pCR after neoadjuvant therapy is a robust, independent prognostic marker in GEA and is associated with more than double long-term survival compared with nonresponders. While adjuvant chemotherapy does not appear to improve outcomes in patients achieving pCR, it remains beneficial in those with incomplete/partial or absent PR after neoadjuvant chemotherapy. These findings support a response-adapted approach to perioperative treatment strategies in GEA.